Bone marrow (BM) hematopoietic stem cells (HSC) comprise an active pool that divides regularly to regenerate the hematopoietic tissue, and a dormant reserve that divides very infrequently (once every 25 weeks) and contains most of the hematopoietic reconstitution activity in serial transplantation assays. Low blood perfusion is a defining characteristic of niches harbouring quiescent HSC in the BM. Quiescent HSC able to serially transplant preferentially reside in niches poorly perfused by the blood, whereas active HSC reside in more perfused niches and have limited self-renewal potential in serial transplantations. Low perfusion results in decreased O2 supply and hypoxia. Hematopoietic cells respond to hypoxia via the transcription factor HIF-1α which is stable and active when oxygen is below 2%. When O2 exceeds 2%, HIF-1α protein is hydroxylated on two proline residues by O2-dependant prolylhydroxylase domain (PHD) enzymes which trigger proteasomal degradation. Small synthetic PHD inhibitors stabilised HIF-1α protein in BM leukocytes and increased HSC quiescence in the BM. Furthermore, PHD inhibitor treatment before 9.0Gy sublethal irradiation accelerated blood cell recovery and increased 89-fold the survival of long-term reconstituting HSC in the BM. Therefore HIF-1α protein stabilisation in poorly perfused niches is an essential promoter of HSC quiescence. We then investigated the role of HIF-1α in therapeutic HSC mobilisation in response to G-CSF. To demonstrate the role of HIF-1α in HSC mobilisation, we generated mice in which the Hif1a gene can be specifically deleted in HSC in a tamoxifen-inducible manner. Hif1a gene deletion in HSC prevented their mobilisation in response to G-CSF. Conversely, additional stabilisation of HIF-1α protein by administering PHD inhibitors in wild-type mice enhanced 20-fold HSC mobilisation in response to G-CSF. In conclusion niche perfusion and HIF-1α are essential regulators of HSC quiescence and trafficking, and HIF-1α protein can be pharmacologically stabilised to promote HSC quiescence, radio-resistance and mobilisation in vivo.